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基本情報
登録情報 | データベース: EMDB / ID: EMD-2712 | |||||||||
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タイトル | Structure of the RET receptor tyrosine kinase extracellular domain | |||||||||
![]() | Reconstruction of a reconstituted mammalian RETecd-GDNF-GFRa1 ternary (mTC) complex | |||||||||
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![]() | vertebrate development / human diseases / RET-GFL-GFRa complex | |||||||||
機能・相同性 | ![]() chemoattractant activity involved in axon guidance / mesenchymal to epithelial transition involved in metanephros morphogenesis / dorsal spinal cord development / postsynaptic membrane organization / positive regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis / ureteric bud formation / positive regulation of ureteric bud formation / regulation of semaphorin-plexin signaling pathway / postganglionic parasympathetic fiber development / positive regulation of monooxygenase activity ...chemoattractant activity involved in axon guidance / mesenchymal to epithelial transition involved in metanephros morphogenesis / dorsal spinal cord development / postsynaptic membrane organization / positive regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis / ureteric bud formation / positive regulation of ureteric bud formation / regulation of semaphorin-plexin signaling pathway / postganglionic parasympathetic fiber development / positive regulation of monooxygenase activity / glial cell-derived neurotrophic factor receptor activity / glial cell-derived neurotrophic factor receptor binding / RET signaling / GDF15-GFRAL signaling pathway / Peyer's patch morphogenesis / positive regulation of metanephric glomerulus development / posterior midgut development / ureter maturation / embryonic epithelial tube formation / glial cell-derived neurotrophic factor receptor signaling pathway / lymphocyte migration into lymphoid organs / : / regulation of morphogenesis of a branching structure / membrane protein proteolysis / neurotrophin receptor activity / positive regulation of peptidyl-serine phosphorylation of STAT protein / regulation of dopamine uptake involved in synaptic transmission / Formation of the ureteric bud / positive regulation of neuron maturation / neuron cell-cell adhesion / Formation of the nephric duct / enteric nervous system development / peristalsis / positive regulation of branching involved in ureteric bud morphogenesis / positive regulation of dopamine secretion / sympathetic nervous system development / peripheral nervous system development / innervation / organ induction / plasma membrane protein complex / regulation of stem cell differentiation / commissural neuron axon guidance / neuron maturation / metanephros development / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / NCAM1 interactions / mRNA stabilization / positive regulation of cell adhesion mediated by integrin / RAF/MAP kinase cascade / neural crest cell migration / ureteric bud development / branching involved in ureteric bud morphogenesis / regulation of axonogenesis / response to pain / homophilic cell adhesion via plasma membrane adhesion molecules / positive regulation of cell size / RET signaling / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / transmembrane receptor protein tyrosine kinase activity / regulation of cell adhesion / embryonic organ development / cellular response to retinoic acid / NPAS4 regulates expression of target genes / multivesicular body / adult locomotory behavior / kidney development / axon guidance / receptor protein-tyrosine kinase / positive regulation of cell differentiation / growth factor activity / neuron differentiation / receptor tyrosine kinase binding / activation of cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of neuron projection development / integrin binding / male gonad development / positive regulation of peptidyl-tyrosine phosphorylation / MAPK cascade / neuron projection development / cell migration / retina development in camera-type eye / regulation of gene expression / signaling receptor activity / nervous system development / RAF/MAP kinase cascade / protein tyrosine kinase activity / negative regulation of neuron apoptotic process / receptor complex / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / endosome membrane / early endosome / positive regulation of cell migration / response to xenobiotic stimulus / protein phosphorylation / external side of plasma membrane / axon / signaling receptor binding / neuronal cell body / positive regulation of cell population proliferation 類似検索 - 分子機能 | |||||||||
生物種 | ![]() ![]() ![]() | |||||||||
手法 | 単粒子再構成法 / ネガティブ染色法 / 解像度: 24.0 Å | |||||||||
![]() | Goodman K / Kjaer S / Beuron F / Knowles P / Nawrotek A / Burns E / Purkiss A / George R / Santoro M / Morris EP / McDonald NQ | |||||||||
![]() | ![]() タイトル: RET recognition of GDNF-GFRα1 ligand by a composite binding site promotes membrane-proximal self-association. 著者: Kerry M Goodman / Svend Kjær / Fabienne Beuron / Phillip P Knowles / Agata Nawrotek / Emily M Burns / Andrew G Purkiss / Roger George / Massimo Santoro / Edward P Morris / Neil Q McDonald / ![]() ![]() 要旨: The RET receptor tyrosine kinase is essential to vertebrate development and implicated in multiple human diseases. RET binds a cell surface bipartite ligand comprising a GDNF family ligand and a ...The RET receptor tyrosine kinase is essential to vertebrate development and implicated in multiple human diseases. RET binds a cell surface bipartite ligand comprising a GDNF family ligand and a GFRα coreceptor, resulting in RET transmembrane signaling. We present a hybrid structural model, derived from electron microscopy (EM) and low-angle X-ray scattering (SAXS) data, of the RET extracellular domain (RET(ECD)), GDNF, and GFRα1 ternary complex, defining the basis for ligand recognition. RET(ECD) envelopes the dimeric ligand complex through a composite binding site comprising four discrete contact sites. The GFRα1-mediated contacts are crucial, particularly close to the invariant RET calcium-binding site, whereas few direct contacts are made by GDNF, explaining how distinct ligand/coreceptor pairs are accommodated. The RET(ECD) cysteine-rich domain (CRD) contacts both ligand components and makes homotypic membrane-proximal interactions occluding three different antibody epitopes. Coupling of these CRD-mediated interactions suggests models for ligand-induced RET activation and ligand-independent oncogenic deregulation. | |||||||||
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画像 | ![]() | 71.4 KB | ||
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文書・要旨 | ![]() | 202.2 KB | 表示 | ![]() |
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文書・詳細版 | ![]() | 201.3 KB | 表示 | |
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「今月の分子」の関連する項目 |
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ファイル | ![]() | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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注釈 | Reconstruction of a reconstituted mammalian RETecd-GDNF-GFRa1 ternary (mTC) complex | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 4.34 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
CCP4マップ ヘッダ情報:
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試料の構成要素
-全体 : Reconstituted mammalian RETecd-GDNF-GFRa1 ternary complex
全体 | 名称: Reconstituted mammalian RETecd-GDNF-GFRa1 ternary complex |
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要素 |
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-超分子 #1000: Reconstituted mammalian RETecd-GDNF-GFRa1 ternary complex
超分子 | 名称: Reconstituted mammalian RETecd-GDNF-GFRa1 ternary complex タイプ: sample / ID: 1000 詳細: Monodisperse. Measured mass difference with theoretical MW corresponds to glycosylation. 集合状態: Hexamer / Number unique components: 3 |
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分子量 | 実験値: 340 KDa / 理論値: 260 KDa / 手法: SEC-MALS |
-分子 #1: RET receptor tyrosine kinase
分子 | 名称: RET receptor tyrosine kinase / タイプ: protein_or_peptide / ID: 1 / Name.synonym: RET / コピー数: 2 / 組換発現: Yes |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 80 KDa |
組換発現 | 生物種: ![]() ![]() 組換株: Lec8 |
-分子 #2: GDNF receptor alpha
分子 | 名称: GDNF receptor alpha / タイプ: protein_or_peptide / ID: 2 / コピー数: 2 / 組換発現: Yes |
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由来(天然) | 生物種: ![]() ![]() |
分子量 | 理論値: 40 KDa |
組換発現 | 生物種: ![]() ![]() |
-分子 #3: glial-cell-line-derived neurotrophic factor
分子 | 名称: glial-cell-line-derived neurotrophic factor / タイプ: protein_or_peptide / ID: 3 / Name.synonym: GDNF / 詳細: from Amgen (USA) / コピー数: 2 / 組換発現: Yes |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 10 KDa |
-実験情報
-構造解析
手法 | ネガティブ染色法 |
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![]() | 単粒子再構成法 |
試料の集合状態 | particle |
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試料調製
濃度 | 0.03 mg/mL |
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緩衝液 | pH: 8 / 詳細: 20 mM Tris HCl, 300 mM NaCl, 1 mM Ca++ |
染色 | タイプ: NEGATIVE 詳細: Samples were applied to glow-discharged grids and stained with 2% uranyl acetate |
グリッド | 詳細: quantifoil (R1.2/1.3) coated with a thin carbon layer, glow discharge in air. |
凍結 | 凍結剤: NONE / 装置: OTHER |
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電子顕微鏡法
顕微鏡 | FEI TECNAI F20 |
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日付 | 2012年11月8日 |
撮影 | カテゴリ: CCD フィルム・検出器のモデル: TVIPS TEMCAM-F415 (4k x 4k) 実像数: 1200 / 平均電子線量: 100 e/Å2 / ビット/ピクセル: 16 |
電子線 | 加速電圧: 200 kV / 電子線源: ![]() |
電子光学系 | 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD / 最小 デフォーカス(公称値): 0.9 µm / 倍率(公称値): 80000 |
試料ステージ | 試料ホルダーモデル: SIDE ENTRY, EUCENTRIC |
実験機器 | ![]() モデル: Tecnai F20 / 画像提供: FEI Company |
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画像解析
詳細 | The particles were selected manually. The starting model was calculated from reference-free classes using angular reconstitution methods and further refined by projection matching. |
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最終 再構成 | 想定した対称性 - 点群: C2 (2回回転対称) / アルゴリズム: OTHER / 解像度のタイプ: BY AUTHOR / 解像度: 24.0 Å / 解像度の算出法: OTHER ソフトウェア - 名称: IMAGIC, SPIDER, in-house, software 使用した粒子像数: 8519 |
最終 2次元分類 | クラス数: 975 |